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WO2000034231A1 - Echafaudages moleculaires comprenant des liaisons carbamate servant de modeles - Google Patents

Echafaudages moleculaires comprenant des liaisons carbamate servant de modeles Download PDF

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Publication number
WO2000034231A1
WO2000034231A1 PCT/US1999/029339 US9929339W WO0034231A1 WO 2000034231 A1 WO2000034231 A1 WO 2000034231A1 US 9929339 W US9929339 W US 9929339W WO 0034231 A1 WO0034231 A1 WO 0034231A1
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compound
group
carbon atoms
groups
compound according
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PCT/US1999/029339
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English (en)
Inventor
David S. Jones
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La Jolla Pharmaceutical Company
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Application filed by La Jolla Pharmaceutical Company filed Critical La Jolla Pharmaceutical Company
Priority to AU20496/00A priority Critical patent/AU775925B2/en
Priority to CA002353462A priority patent/CA2353462A1/fr
Priority to KR1020017007221A priority patent/KR20010093813A/ko
Priority to EP99964209A priority patent/EP1137628A1/fr
Priority to JP2000586680A priority patent/JP2002531541A/ja
Publication of WO2000034231A1 publication Critical patent/WO2000034231A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/68—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/69—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • This invention pertains generally to valency molecules.
  • the present invention pertains to valency platforms comprising carbamate linkages, which molecules have the structure of any one of Formulae I, II, or III, shown in Figure 1.
  • the present invention pertains to valency platforms comprising carbamate linkages, which molecules have the structure of any one of Formulae IV, V, or VI, shown in Figure 8.
  • the present invention also pertains to methods of preparing such valency molecules, conjugates comprising such valency molecules, and methods of preparing such conjugates.
  • a “valency platform” is a molecule with one or more (and typically multiple) attachment sites which can be used to covalently attach biologically active molecules of interest to a common scaffold.
  • the attachment of biologically active molecules to a common scaffold provides multivalent conjugates in which multiple copies of the biologically active molecule are covalently linked to the same platform.
  • a “defined” or “chemically defined” valency platform is a platform with defined structure, thus a defined number of attachment points and a defined valency.
  • a defined valency platform conjugate is a conjugate with defined structure and has a defined number of attached biologically active compounds.
  • biologically active molecules include oligonucleotides, peptides, polypeptides, proteins, antibodies, saccharides, polysaccharides, epitopes, mimotopes, drugs, and the like. In general, biologically active compounds interact specifically with proteinaceous receptors.
  • the valency platforms of the present invention reflect a new class of valency platforms which comprise a carbamate linkage, as shown, for example, in Formulae I, II, and III in Figure 1 and in Formulae IN, V, and VI in Figure 8.
  • One aspect of the present invention pertains to a valency platform compound having the structure of one of the following formulae: Formula I
  • n is a positive integer from 1 to 10; y 1 , y 2 , and y 3 are independently 1 or 2;
  • J independently denotes either an oxygen atom or a covalent bond
  • R c is selected from the group consisting of: hydrocarbyl groups having from 1 to 20 carbon atoms; organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms; organic groups consisting only of carbon, oxygen, nitrogen, and hydrogen atoms, and having from 1 to 20 carbon atoms; organic groups consisting only of carbon, oxygen, sulfur, and hydrogen atoms, and having from 1 to 20 carbon atoms; each G 1 , G 2 , and G 3 is independently selected from the group consisting of: hydrocarbyl groups having from 1 to 20 carbon atoms; organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms; organic groups consisting only of carbon, oxygen, nitrogen, and hydrogen atoms, and having from 1 to 20 carbon atoms; each R N is independently selected from the group consisting of: hydrogen; linear or branched alkyl groups having from 1 to 15 carbon atoms; alkyl groups comprising an alicyclic structure and having from
  • each R CARB is organic groups comprising from 1 to about 20 carbon atoms
  • each R ESTER is organic groups comprising from 1 to about 20 carbon atoms
  • each group -NR A R B is independently selected from the group consisting of:
  • each monovalent R ⁇ and R B and each divalent R is independently an organic group comprising from.l to 20 carbon atoms, and further comprising a reactive conjugating functional group.
  • said compound has the structure of Formula I. In one embodiment, said compound has the structure of Formula II. In one embodiment, said compound has the structure of Formula III. In one embodiment, said compound has the structure of Formula IV. In one embodiment, n is a positive integer from 2 to 4. In one embodiment, y 1 , y 2 , and y 3 are each 2. In one embodiment, J is an oxygen atom. In one embodiment, J is a covalent bond. In one embodiment, R c is selected from the group consisting of hydrocarbyl groups having from 1 to 20 carbon atoms. In one embodiment, R c is selected from the group consisting of:
  • R c is selected from the group consisting of organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms. In one embodiment, R c is:
  • each G 1 , G 2 , and G 3 is independently selected from the group consisting of hydrocarbyl groups having from 1 to 20 carbon atoms. In one embodiment, each G 1 , G 2 , and G 3 is -(CH 2 ) q - wherein q is a positive integer from 1 to 20. In one embodiment, each G 1 , G 2 , and G 3 is independently selected from the group consisting of organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms. In one embodiment, each G 1 ,
  • G 2 , and G 3 is:
  • R N is independently selected from the group consisting of -H, -CH 3 , and -CH 2 CH 3 .
  • each group -NR A R B is independently selected from the group consisting of:
  • Another aspect of the present invention pertains to a valency platform compound having the structure of one of the following formulae:
  • n is a positive integer from 1 to 10; y 1 , y 2 , and y 3 are independently a positive integer from 1 to 10;
  • J independently denotes either an oxygen atom or a covalent bond
  • R c is selected from the group consisting of: hydrocarbyl groups having from 1 to 20 carbon atoms; organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms; organic groups consisting only of carbon, oxygen, nitrogen, and hydrogen atoms, and having from 1 to 20 carbon atoms; organic groups consisting only of carbon, oxygen, sulfur, and hydrogen atoms, and having from 1 to 20 carbon atoms; each G 1 , G 2 , and G 3 is independently selected from the group consisting of: hydrocarbyl groups having from 1 to 20 carbon atoms; organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms; organic groups consisting only of carbon, oxygen, nitrogen, and hydrogen atoms, and having from 1 to 20 carbon atoms; each R N is independently selected from the group consisting of: hydrogen; linear or branched alkyl groups having from 1 to 15 carbon atoms; alkyl groups comprising an alicyclic structure and having from
  • each R CARB is organic groups comprising from 1 to about 20 carbon atoms
  • each R ESTER is organic groups comprising from 1 to about 20 carbon atoms
  • each group -NR A R B is independently selected from the group consisting of:
  • each monovalent R A and R B and each divalent R ⁇ is independently an organic group comprising from 1 to 20 carbon atoms, and further comprising a reactive conjugating functional group.
  • said compound has the structure of Formula V. In one embodiment, said compound has the structure of Formula VI. In one embodiment, said compound has the structure of Formula VII. In one embodiment, n is a positive integer from 2 to 4. In one embodiment, y 1 , y 2 , and y 3 are each 2. In one embodiment, J is an oxygen atom. In one embodiment, J is a covalent bond. In one embodiment, R c is selected from the group consisting of hydrocarbyl groups having from 1 to 20 carbon atoms. In one embodiment, R c is selected from the group consisting of:
  • R c is selected from the group consisting of organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms. In one embodiment. R c is:
  • each G 1 , G 2 , and G 3 is independently selected from the group consisting of hydrocarbyl groups having from 1 to
  • each G 1 , G 2 , and G 3 is selected from the group consisting of:
  • each G 1 , G 2 , and G 3 is independently selected from the group consisting of organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms.
  • each R N is independently selected from the group consisting of -H, -CH 3 , and -CH 2 CH 3 .
  • each group -NR A R B is independently selected from the group consisting of:
  • Another aspect of the present invention pertains to methods of preparing a valency platform compound, as described herein.
  • Another aspect of the present invention pertains to a conjugate comprising a valency platform compound, as described herein, covalently linked to one or more biologically active molecules.
  • said biologically active molecules are selected from the group consisting of: oligonucleotides, peptides, polypeptides, proteins, antibodies, saccharides, polysaccharides, epitopes, mimotopes, and drugs.
  • Another aspect of the present invention pertains to methods of preparing conjugates, as described herein.
  • Figure 1 shows certain valency platforms of the present invention, specifically, those having the structure of Formulae I, II, and III.
  • Figure 2 shows certain valency platforms of the present invention, specifically, some of those having the structure of Formula I.
  • Figure 3 shows certain valency platforms of the present invention, specifically, some of those having the structure of Formula I.
  • Figure 4 shows certain valency platforms of the present invention, specifically, some of those having the structure of Formula II.
  • Figure 5 shows certain valency platforms of the present invention, specifically, some of those having the structure of Formula II.
  • Figure 6 shows certain valency platforms of the present invention, specifically, some of those having the structure of Formula III.
  • Figure 7 shows certain valency platforms of the present invention, specifically, some of those having the structure of Formula I.
  • Figure 8 shows certain valency platforms of the present invention, specifically, those having the structure of Formulae VI, V, and VI.
  • Figure 9 shows a synthetic scheme for a simple example of "core propagation" to obtain valency platforms of the present invention.
  • Figure 10 shows synthetic schemes for the preparation of certain intermediates useful in the preparation of valency platforms of the present invention.
  • Figures 11 A and 1 IB show synthetic schemes for the preparation of valency platform molecules of the present invention.
  • Figures 12A and 12B show synthetic schemes for the preparation of valency platform molecules of the present invention.
  • Figure 13 shows a synthetic schemes for the preparation of valency platform molecules of the present invention.
  • Figures 14A and 14B show synthetic schemes for the preparation of valency platform molecules of the present invention.
  • Figure 15 shows a synthetic schemes for the preparation of valency platform molecules of the present invention.
  • Figures 16A and 16B show synthetic schemes for the preparation of valency platform molecules of the present invention.
  • Figures 17A, 17B, 17C, and 17D show synthetic schemes for the preparation of valency platform molecules of the present invention.
  • Figures 18A and 18B show synthetic schemes for the preparation of valency platform molecules of the present invention.
  • Figure 19 shows a synthetic schemes for the preparation of valency platform molecules of the present invention.
  • Figures 20A and 20B show synthetic schemes for the preparation of valency platform molecules of the present invention.
  • Figure 21 shows the structure of examples of two carbamate compounds 39b and 39c.
  • valency molecules are provided that comprise branches, wherein at each branch, the molecule branches into two or more arms.
  • the arms also may comprise branches.
  • the valency molecule further comprises terminal groups on arms extending from the branches. Exemplary terminal groups are reactive conjugating functional groups. This is illustrated in the Figures, for example, by compound H in Figure 1 IB, which includes 6 branches and 8 terminal CBZ-protected amino groups.
  • composition comprising valency molecules, wherein each valency molecule comprises at least two branches, at least four terminal groups, and at least 2 carbamate linkages; and wherein said valency molecules have a polydispersity less than about 1.2, or for example, less than about 1.07.
  • the valency molecules further can comprise, for example, at least 4 carbamate linkages, at least 4 branches and at least 8 terminal groups.
  • the valency molecules may be dendrimers.
  • the number of branches in the valency molecule may vary and may be, for example, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 16, 32, 64, 100 or more branches.
  • the number of branches can be, for example, 2-64, 2-32, 2-16, 4-64, 4-32, 8-64, or 8-32.
  • the number of branches may be, for example, at least 2, at least 4, at least 6, or at least 8.
  • the number of carbamate linkages may vary.
  • the valency molecule can include, for example, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 15, 16, 18, 20, 24, 29, 32, 64, 100 or more carbamate linkages.
  • the number of carbamate linkages can be, for example, 2-64, 2-32, 2- 16, 4-64, 4-32, 8-64, or 8-32.
  • the number of carbamate linkages may be, for example, at least 2, at least 4, at least 6, or at least 8.
  • Each valency molecule can comprise for example, 1 to 100, e.g, 1-50 terminal groups.
  • the valency molecule may comprise 4, 6, 8, 9, 10, 12, 14, 15, 16, 18, 20, 21, 24, 29, or 32 or more terminal groups.
  • the valency molecule may comprise at least 4 terminal groups, or at least 6 terminal groups, or at least 8 terminal groups.
  • the valency molecule in one embodiment has, for example, 4-16, 4-32, 4-64, 8-32, 8-64, 12-32 or 12-64 terminal groups.
  • the said terminal groups are in one embodiment identical.
  • valency molecules examples include valency platform molecules.
  • Valency molecules can be made as described herein for the synthesis of valency platform molecules.
  • the present invention pertains to valency platforms comprising carbamate linkages and methods for the preparation of such platforms.
  • Particular advantages of the present invention include, but are not limited to, (1) the ease of synthesis of valency platform molecules, (2) the metabolic stability of the carbamate linkages in the valency platform, (3) the ability to adjust the length and water solubility of the "arms" of the valency platform by using, for example, different dialcoholamines, (4) the ability to further attenuate the properties of the valency platform by choice of the core group (e.g., attachment of solubilizing groups, chromophores, reporting groups, targeting groups, and the like).
  • a composition comprising valency platform molecules, wherein each valency platform molecule comprises at least 2 carbamate linkages and at least 4 reactive conjugating functional groups; and wherein said valency platform molecules have a polydispersity less than about 1.2, or optionally a polydispersity less than about 1.07.
  • the valency platform molecules of the composition may comprise, for example, at least 4 carbamate linkages and at least 8 reactive functional groups.
  • the valency platform molecules comprise at least 4 identical reactive conjugating functional groups.
  • the valency platform molecules comprise, for example, 2-32 carbamate linkages and 4-64 reactive functional groups.
  • the valency platform molecules optionally may be linked to one or more biologically active molecules, e.g., via the reactive conjugating functional groups.
  • the valency molecules such as valency platform molecules have the advantage of having a substantially homogeneous (i.e., uniform) molecular weight (as opposed to poly disperse molecular weight), and are thus "chemically defined". Accordingly, a population of these molecules (or conjugates thereof) are substantially monodisperse, i.e., have a narrow molecular weight distribution.
  • a measure of the breadth of distribution of molecular weight of a sample of a platform molecule is the polydispersity of the sample. Polydispersity is used as a measure of the molecular weight homogeneity or nonhomogeneity of a polymer sample.
  • Polydispersity is calculated by dividing the weight average molecular weight (Mw) by the number average molecular weight (Mn). The value of Mw/Mn is unity for a perfectly monodisperse polymer. Polydispersity (Mw/Mn) is measured by methods available in the art, such as gel permeation chromatography.
  • the polydispersity (Mw/Mn) of a sample of valency molecules is preferably less than 2, more preferably, less than 1.5, or less than 1.2, less than 1.1, less than 1.07, less than 1.02, or, e.g., about 1.05 to 1.5 or about 1.05 to 1.2.
  • Typical polymers generally have a polydispersity of 2-5, or in some cases, 20 or more.
  • the low polydispersity property of the valency platform molecules include improved biocompatibility and bioavailability since the molecules are substantially homogeneous in size, and variations in biological activity due to wide variations in molecular weight are minimized.
  • the low polydispersity molecules thus are pharmaceutically optimally formulated and easy to analyze.
  • valency platform molecules for example, the number of attachment sites, e.g., reactive conjugating functional groups, is controlled and defined.
  • Each valency platform molecule can comprise for example, 1 to 100, e.g, 1-50 attachment sites.
  • the valency platform molecule may comprise 4, 6, 8, 9, 10, 12, 14, 15, 16, 18, 20,
  • the valency platform molecule may comprise at least 4 attachment sites, or at least 6 attachment sites, or at least 8 attachment sites.
  • the valency platform molecule in one embodiment has, for example, 4- 16, 4-32, 4-64, 8-32, 8-64, 12-32 or 12-64 attachment sites.
  • the said attachment sites are in one preferred embodiment identical.
  • the number of carbamate linkages may vary.
  • the valency platform molecule can include, for example, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 15, 16, 18, 20, 24, 29, 32, 64, 100 or more carbamate linkages.
  • the number of carbamate linkages can be, for example, 2-64, 2- 32, 2- 16, 4-64, 4-32, 8-64, or 8-32.
  • the number of carbamate linkages may be, for example, at least 2, at least 4, at least 6, or at least 8.
  • the valency platform molecule can comprise various combinations of the carbamate linkages and attachment sites such as reactive functional groups depending on the method of preparation, for example, 2-32 , e.g., 2-16 carbamate linkages; and 4-64, e.g., 4-32 reactive functional groups.
  • the present invention pertains to a valency platform having the structure of Formula I, as shown in Figure 1.
  • n is a positive integer from 1 to 10, more preferably from 1 to 5. In one embodiment, n is a positive integer from 2 to 10, more preferably from 2 to 5. In one embodiment, n is 1. In one embodiment, n is 2. In one embodiment, n is 3. In one embodiment, n is 4.
  • y is 1 or 2, and the subscript "2-y is therefore 1 or 0, respectively.
  • J independently denotes either an oxygen atom (i.e., -O-) or a covalent bond (i.e., no atom is present).
  • a covalent bond i.e., no atom is present.
  • J is -O-
  • J is a covalent bond
  • R c denotes a "core group,” that is, an organic group which forms the core of the valency platform, and to which one or more sidechains is attached.
  • the valency of the core group is determined by n. If n is 1, then R c is monovalent; if n is 2, then R c is divalent; if n is 3, then R c is trivalent; if n is 4, then R c is tetravalent, and so on.
  • R c is a hydrocarbyl group (i.e., consisting only of carbon and hydrogen) having from 1 to 20 carbon atoms, more preferably from 1 to 10 carbon atoms, still more preferably from 1 to 6 carbon atoms.
  • R c is linear.
  • R c is branched.
  • R c comprises a cyclic structure.
  • R c is cyclic.
  • R c is fully saturated.
  • Rc is partially unsaturated.
  • R c comprises an aromatic structure.
  • R c is aromatic.
  • R c is -CH 2 -.
  • R c is
  • R c is -CH 2 CH 2 CH 2 -. In one embodiment, R c is:
  • R c is:
  • R c is an organic group consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms, more preferably from 1 to 10 carbon atoms, still more preferably from 1 to 6 carbon atoms.
  • R c is derived from a polyalkylene oxide group.
  • R c is derived from a polyethylene oxide group.
  • R c is a divalent polyalkylene oxide group.
  • R c is a divalent polyethylene oxide group. In one embodiment, R c is a divalent polypropylene oxide group. In one embodiment, R c is:
  • p is a positive integer from 2 to about 200, more preferably from 2 to about 50, more preferably from 2 to about 20, more preferably from 2 to about 10, more preferably from 2 to about 6. In one embodiment, p is 2. In one embodiment, p is 3. In one embodiment, p is 4. In one embodiment, p is 5. In one embodiment, p is 6.
  • R c is an organic group consisting only of carbon, oxygen, nitrogen, and hydrogen atoms, and having from 1 to 20 carbon atoms, more preferably from
  • core groups 1 to 10 carbon atoms, still more preferably from 1 to 6 carbon atoms.
  • core groups include, but are not limited to, those derive from the "core compounds” described below which consist only of carbon, oxygen, nitrogen, and hydrogen atoms.
  • R c is an organic group consisting only of carbon, oxygen, sulfur, and hydrogen atoms, and having from 1 to 20 carbon atoms, more preferably from 1 to 10 carbon atoms, still more preferably from 1 to 6 carbon atoms.
  • core groups include, but are not limited to, those derive from the "core compounds" described below which consist only of carbon, oxygen, sulfur, and hydrogen atoms.
  • G 1 denotes an organic "linker group.”
  • G 1 is a hydrocarbyl group (i. e. , consisting only of carbon and hydrogen) having from 1 to 20 carbon atoms, more preferably from 1 to 10 carbon atoms, still more preferably from 1 to 6 carbon atoms.
  • G 1 is linear.
  • G' is branched.
  • G 1 comprises a cyclic structure.
  • G 1 is cyclic.
  • G 1 is fully saturated.
  • G 1 is partially unsaturated.
  • G 1 comprises an aromatic structure.
  • G 1 is aromatic.
  • G 1 is divalent.
  • R c is -(CH 2 ) q - wherein q is a positive integer from 1 to about 20, more preferably from 1 to about 10, more preferably from 1 to about 6, more preferably from 1 to about 4.
  • G 1 is -CH 2 -.
  • G 1 is -CH 2 CH 2 -.
  • G ! is -CH 2 CH 2 CH 2 -.
  • G 1 is an organic group consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 20 carbon atoms, more preferably from 1 to 10 carbon atoms, still more preferably from 1 to 6 carbon atoms.
  • G 1 is derived from a polyalkylene oxide group.
  • G 1 is a divalent polyalkylene oxide group.
  • G 1 is a divalent polyethylene oxide group.
  • G 1 is a divalent polypropylene oxide group.
  • G 1 is:
  • p is a positive integer from 2 to about 200, more preferably from 2 to about 50, more preferably from 2 to about 20, more preferably from 2 to about 10, more preferably from 2 to about 6. In one embodiment, p is 2. In one embodiment, p is 3. In one embodiment, p is 4. In one embodiment, p is 5. In one embodiment, p is 6.
  • G 1 is an organic group consisting only of carbon, oxygen, nitrogen, and hydrogen atoms, and having from 1 to 20 carbon atoms, more preferably from
  • R N denotes a nitrogen substituent, more specifically, an amino substituent.
  • R N if present, is hydrogen (i.e., -H).
  • R N if present, is a linear or branched alkyl group having from 1 to 15 carbon atoms, more preferably from 1 to 10 carbon atoms, more preferably from 1 to 6 carbon atoms.
  • R N if present, is an alkyl group comprising an alicyclic structure and having from 1 to 15 carbon atoms, more preferably from 1 to 10 carbon atoms, more preferably from 1 to 6 carbon atoms.
  • R N if present, is or comprises an aromatic group.
  • R N if present, is or comprises a heteroaromatic group. In one embodiment, R N , if present, is or comprises an aromatic group having from 6 to 20 carbon atoms, more preferably from 6 to 15 carbon atoms, more preferably from 6 to 10 carbon atoms. In one embodiment, R N , if present, is or comprises a heteroaromatic group having from 3 to 20 carbon atoms, more preferably from 3 to 15 carbon atoms, more preferably from 3 to 10 carbon atoms. In one embodiment, R N is selected from the group consisting of
  • each R CARB is a carbonate substituent or an activated carbonate substituent.
  • Many carbonate substituents are well known in the art, including, for example, organic groups comprising from 1 to about 20 carbon atoms, including, for example, primary, secondary, and tertiary, substituted and unsubstituted, alkyl and aryl groups having from 1 to about 20 carbon atoms.
  • Other examples of carbonate groups include those described herein for R N .
  • Still other examples of carbonate groups include those described below for activated carbonates.
  • each R ESTER is an ester substituent or an activated ester substituent.
  • ester and activated ester substituents are well known in the art, including, for example, organic groups comprising from 1 to about 20 carbon atoms, including, for example, primary, secondary, and tertiary alkyl and aryl groups having from
  • R ESTER examples include, but are not limited to, -CH 3 (to give an acetate group), -CH 2 SH (to give a mercaptoacetate group), and -CH 2 C 6 H 5 , to give a benzoate group).
  • Z is -NR A R B and denotes an amino group.
  • the amino group may be unsubstituted, in which case, R A and R B are both hydrogen (i.e., -NR A R B is -NH 2 ).
  • the amino group may be monosubstituted, in which case R B is hydrogen (/ ' . e. , -NR A R B is - NHR A ).
  • the amino group may be disubstituted.
  • R A and R B may be separate moieties, as in -NR ⁇ R B , or R A and R B may be covalently linked together and form a divalent substituent, denoted R ⁇ (i.e., -NR A R B is -NR AB ).
  • R ⁇ i.e., -NR A R B is -NR AB
  • each group - NR A R B is independently selected from the group consisting of: -NH 2 , -NHR A , -NHR A R B , and -NR ⁇ , wherein each monovalent R A and R B and each divalent R ⁇ is independently an organic group comprising from 1 to 20 carbon atoms, and further comprising a reactive conjugating functional group.
  • each group -NR A R B is independently selected from the group consisting of: -NHR A , -NHR A R B , and -NR* 8 .
  • R A , R B , and R 8 preferably comprise a reactive conjugating functional group.
  • each X is independently F, CI, Br, I, or other good leaving group
  • each R* 1 ⁇ is independently an alkyl group, such as a linear or branched alkyl or cycloalkyl group having from 1 to about 20 carbon atoms
  • each R SUB is independently H or an organic group, such as a linear or branched alkyl group, or a cycloalkyl group having from 1 to about 20 carbon atoms, an aryl group having from 6 to about 20 carbon atoms, or an alkaryl group having from 7 to about 30 carbon atoms
  • each P ESTER - s i n d e p enc ⁇ en iy an organic group having from 1 to about 20 carbon atoms, including, for example, primary, secondary, and tertiary alkyl and aryl groups having from 1 to about 20 carbon atoms
  • each R B is independently a organic group, such as an organic group comprising 1 to 50 atoms
  • the reactive conjugating functional group is an amino group or a protected amino group.
  • the group -NR A R B comprises an amino group, and has the structure:
  • the group -NR A R B comprises a protected amino group, and has the structure:
  • the group -NR A R B comprises a hydrobromide salt of an amino group, and has the structure:
  • the group -NR A R B comprises a haloacetyl group (where X denotes CI, Br, or I), and has the structure:
  • the group -NR A R B comprises an amino group, and has the structure:
  • n is a positive integer from 1 to about 20, preferably from 1 to about 10, preferably from 1 to about 5.
  • the group -NR A R B comprises a protected amino group, and has the structure: 0 CH 3 s ⁇ — NH— CH 2 CH 2 — NH— C 'I— O— C I — CH 3
  • the group -NR A R B comprises an amino group, and has the structure: NH _i_ CH2CH2 ⁇ )4_)_-C C H H2? C C H H22 —— r N H 2 / n wherein n is a positive integer from 1 to about 20, preferably from 1 to about 10, preferably from 1 to about 5.
  • FIGS 2, 3, and 7 Examples of valency platforms having the structure of Formula I are shown in Figures 2, 3, and 7.
  • the number of terminal groups -NR ⁇ R B is given by "n*y ⁇ "
  • the structure When “n*y'” is 8, the structure may conveniently be referred to as a "octameric” structure.
  • When “n*y'” is 16 the structure may conveniently be referred to as a "hexadecameric” structure.
  • Examples of compounds having the structure of Formula I where Z is -H include, but are not limited to, compounds 21_, 24, 27a, 29, 32, and 38, described in the Examples below.
  • Examples of compounds having the structure of Formula I where Z is -NR A R B include, but are not limited to, compounds 23, 23a, 26, 26a, 3J_, 31a, 34, 34a, 40, 41_, 42, and 5 _, described in the Examples below.
  • the present invention pertains to a valency platform having the structure of Formula II, as shown in Figure 1.
  • n, R c , J, R A , R B , y 1 , R N , G 1 , and Z are as defined above for Formulae I.
  • y 2 and G 2 are as defined above for y 1 and G', respectively.
  • FIGs 4 and 5 Examples of valency platforms having the structure of Formula II are shown in Figures 4 and 5.
  • the number of terminal groups -NR A R B is given by "n*y'*y 2 .”
  • n*y 1 *y 2 " is 4 the structure may conveniently be referred to as a "tetrameric” structure.
  • n*y'*y 2 " is 8 the structure may conveniently be referred to as a "octameric” structure.
  • When "n*y'*y 2 " is 16 the structure may conveniently be referred to as a "hexadecameric” structure.
  • Examples of compounds having the structure of Formula II where Z is -H include, but are not limited to, compounds 35, 43a, and 49a, described in the Examples below.
  • Examples of compounds having the structure of Formula II where Z is -NR A R B include, but are not limited to, compounds 14, 1_5, 20, 20a, 28, 28a, 36, 36a, 44, 44a, and 45, described in the Examples below.
  • the present invention pertains to a valency platform having the structure of Formula III, as shown in Figure 1.
  • n, R c , J, R A , R B , y 1 , y 2 , R N , G 1 , G 2 , and Z are as defined above for Formulae I and II.
  • y 3 and G 3 are as defined above for y 1 and G 1 , respectively.
  • FIG. 6 Examples of a valency platform having the structure of Formula III is shown in Figure 6.
  • the number of terminal groups -NR A R B is given by "n*y'*y 2 *y 3 .”
  • n*y'*y 2 *y 3 4
  • the structure may conveniently be referred to as a "tetrameric” structure.
  • n*y 1 *y 2 *y 3 " is 8 the structure may conveniently be referred to as a "octameric” structure.
  • Formulae IV, V, and VI Formulae IV, V, and VI
  • the present invention pertains to a valency platform having the structure of Formula IV, V, or VI, as shown in Figure 8.
  • n, R c , J, R A , R B , R N , and Z are as defined above for Formulae I through III.
  • compounds of Formulae IV through VI may have branch points at a G group, for example, at G 1 , G 2 , or G 3 , and there may be one, two, three, or more branches, for example, y 1 , y 2 , or y 3 branches.
  • G 1 , G 2 , and G 3 are similar to G 1 , G 2 , and G 3 for Formulae I through III. In a preferred embodiments, these groups are trivalent, tetravalent or higher. In one embodiment, G ! , G 2 , and G 3 are selected from the group consisting of: CH 2 - CH 2 — ⁇ CH 2 — ⁇
  • y 1 , y 2 , and y 3 are positive integers from 1 to about 10, more preferably from 1 to 5, more preferably from 1 to 4, more preferably from 1 to 3, more preferably from 1 to 2.
  • Examples of compounds having the structure of Formula IV where Z is -H include, but are not limited to, compound 46, described in the Examples below.
  • Examples of compounds having the structure of Formula V where Z is -H include, but are not limited to, compound 47a, described in the Examples below.
  • Examples of compounds having the structure of Formula V where Z is -NR A R B include, but are not limited to, compounds 48a, 48b, and 48c, described in the Examples below.
  • the number of termini may be calculated as the product of n, y 1 , y 2 , y 3 , etc., as discussed above.
  • this product is 2 or more. In one embodiment, this product is more than 2. In one embodiment, this product is more than 3. In one embodiment, this product is 4. In one embodiment, this product is 6. In one embodiment, this product is 8. In one embodiment, this product is 16. In one embodiment, this product is 32.
  • the valency platform molecule may be described as "dendritic," owing to the presence of successive branch points. Dendritic valency platform molecules possess multiple termini, typically 4 or more termini. In one embodiment, the valency platform molecule is dendritic and has 4 termini, such as, for example, compounds 23a, 26a, 31a, 34a, 42a, described in the examples below. In one embodiment, the valency platform molecule is dendritic and has 8 termini, such as, for example, compounds J_5, 20a, 28a, 36a, 45, 48c and 5_1_, described in the examples below. In one embodiment, the valency platform molecule is dendritic and has 16 termini.
  • Formulae I through VI are intended to encompass both “symmetric" and “non-symmetric" valency platforms.
  • the valency platform is symmetric.
  • the valency platform is non-symmetric.
  • each of the "n" groups which are pendant from the core group, R c may be the same or may be independently different.
  • Higher generation valency platforms e.g., 4th generation, 5th generation
  • 4th generation valency platforms would have G 4 and y 4
  • 5th generation valency platforms would further have G 5 and y 5 , and so on for successive generations.
  • “hybrid” valency platforms are contemplated, which would include linkages of the sort found in Formulae I through III as well as linkages of the sort found in Formulae IV through VI.
  • the valency platforms of the present invention may be prepared from "core" compounds which comprise one or more (say, j°) hydroxy groups (i.e., -OH).
  • core compounds which comprise one or more (say, j°) hydroxy groups (i.e., -OH).
  • the hydroxyl groups on the core are converted to active carbonate derivatives, such as activated carbonate esters (for example, a js ⁇ r ⁇ -nitrophenylcarbonate ester) and subsequently reacted with a polyhydroxyamine compounds having j 1 hydroxy groups to provide a "first generation" carbamate with j 1 hydroxyl groups for each original hydroxyl group, for a total of j°*j' hydroxyl groups.
  • the resulting hydroxy groups may then also be converted to activated carbonate derivatives, such as activated carbonate esters and subsequently reacted with a polyhydroxyamine compound having j 2 hydroxy groups to provide a "second generation" carbamate with j 2 hydroxyl groups for each j 1 hydroxyl group, for a total of j 0 *j'*j 2 hydroxyl groups.
  • activated carbonate derivatives such as activated carbonate esters
  • an appropriately functionalized compound for example, an mono-protected diamine
  • the valency platforms of the present invention may be prepared from a “segmental approach” in which “segments” are independently synthesized and subsequently attached to a “core” group.
  • an alternative, more efficient "core propagation" process has been developed in which a core group is modified in an iterative process to generate a dendritic structure.
  • the core propagation approach involves fewer steps and is preferred over the segmental approach.
  • the valency platforms of the present invention may be prepared using solid phase synthesis from a hydroxyl containing resin.
  • a hydroxyl group attached to a solid phase by a cleavable linker provides a way of building a dendrimeric scaffold using solid phase synthesis.
  • the ability to prepare scaffolds on the solid phase can be particularly useful for the rapid synthesis of dendrimeric platforms with minimal purification.
  • solid phase dendrimeric platforms can be used to generate combinatorial libraries of multivalent compounds.
  • the synthesis typically begins with an alcohol containing "core compound.”
  • any hydroxyl-containing compound can be used. Examples of alcohol containing "core compounds” having one hydroxyl group (i.e., -OH) include, but are not limited to: methanol,
  • alcohol containing "core compounds” having one hydroxyl group include, but are not limited to, mono-hydroxylamines, such as those described below, for which the amino group may be in a protected form, for example, using a BOC or CBZ protecting group.
  • alcohol containing "core compounds” having two hydroxyl groups include, but are not limited to: ethylene glycol,
  • polyethylene glycol also referred to as PEG
  • n typically from 1 to about
  • alcohol containing "core compounds" having two hydroxyl groups include, but are not limited to, primary or secondary amines having two hydroxyl groups, such as those described below. Again, the amino group may be in a protected form, for example, using a BOC or CBZ protecting group.
  • alcohol containing "core compounds” having three hydroxyl groups include, but are not limited to: phluoroglucinol (also known as 1,3,5-trihydroxybenzene),
  • alcohol containing "core compounds” having three or more hydroxyl groups include, but are not limited to, primary or secondary amines having three hydroxyl groups, such as those described below. Again, the amino group may be in a protected form, for example, using a BOC or CBZ protecting group.
  • alcohol containing "core compounds” having four hydroxyl groups include, but are not limited to: pentaerythritol,
  • alcohol containing “core compounds” include, but are not limited to, those which comprise a sulfhydryl group (i.e., -SH), which may be protected, for example, with a trityl protecting group (i.e., as -S-Tr, that is, -S-C(C 6 H 5 ) 3 ) or as a disulfide (i.e., as -S-SR).
  • a sulfhydryl group i.e., -SH
  • a trityl protecting group i.e., as -S-Tr, that is, -S-C(C 6 H 5 ) 3
  • disulfide i.e., as -S-SR
  • core groups which have a protected sulfhydryl group include, but are not limited to, the following:
  • n is from 1 to about 200, preferably from 1 to about 20.
  • hydroxyl groups on solid phase synthesis resins can be used as core groups to provide dendrimeric carbamate residues on solid phase which can be used to boost the valence of the resin or cleaved off the resin.
  • a Wang resin of the following form may be used:
  • a hydroxy containing core group may be prepared from a corresponding carboxylic acid compound or halocarbonyl compound:
  • Core compounds which possess amino or sulfhydryl groups, which may be protected or unprotected, may be used to covalently attach the resulting valency platform molecule to other molecules of interest, via the core group rather than via the termini, using conjugation methods such as those described herein.
  • the hydroxyl groups of the alcohol containing core group are converted to active carbonate derivatives.
  • the active carbonate derivative in one embodiment has the formula:
  • X is a leaving group such as CI, imidazole or thiolate.
  • the hydroxyl groups of the alcohol can be converted to active active carbonates by reaction of the hydroxyl groups of the alcohol containing core group with a phosgene equivalent.
  • Phosgene equivalents with appropriate reactivity can be selected.
  • the phosgene equivalent has, for example, the structure X,(CO)X 2 where X, and X 2 are both leaving groups.
  • X, and X 2 each independently can be chosen from typical leaving groups in acylation chemistry such as alkoxide, thiolate, halide, and imidazole.
  • the phosgene equivalent is 4-nitrophenylchloroformate.
  • the phosgene equivalent is carbonyldiimidazole.
  • Other exemplary phosgene equivalents include phosgene, N,N'-succinimidylcarbonate, succinimidyl 2,2,2-trichloroethylcarbonate, bis-4-nitrophenylcarbonate, triphosgene,
  • the active carbonate derivative is used to acylate an aminoalcohol on the nitrogen, forming the carbamate bond, then the phosgene again is added to convert the hydroxyl group to another active carbonate derivative.
  • An example of an active carbonate derivative is compound 39c shown in Figure 21.
  • the active carbonate derivative is a carbonate ester.
  • carbonate and carbonate ester are used herein in the conventional sense and relate to species which comprise the following structure:
  • activated carbonate and “activated carbonate ester” are used herein to refer to carbonates for which R 1 is an activating group, and for which the moiety - O-R 1 forms a good leaving group.
  • a particularly preferred class of activated carbonate esters include, but are not limited to /? ⁇ r ⁇ -nitrophenyl carbonate ester compounds of the formula:
  • PNP activated carbonate esters may readily be formed from the corresponding alcohol, R-OH by reaction with PNP chloroformate in the presence of pyridine (C 5 H 5 N) in methylene chloride (CH 2 C1 2 ).
  • Examples of other activated carbonate groups include, but are not limited to, the following:
  • the activated carbonate ester is converted to the corresponding carbamate.
  • the above PNP activated carbonate esters are readily converted to the corresponding carbamates by reaction with an amine.
  • the dendritic structure may be extended by employing a primary or secondary amine having j 1 hydroxy groups. In this way, each original hydroxy group, which led to an activated carbonate ester group, then leads to j 1 hydroxy groups.
  • the PNP activated carbonate ester may be reacted with a primary or secondary dihydroxy amine.
  • primary and secondary amines having two hydroxyl groups include, but are not limited to: diethanolamine,
  • serinol also known as 2-amino-l,3-propanediol
  • the activated carbonate ester is converted to the corresponding carbamate using a monohydroxyamine to maintain valency from one generation to the next yet impart unique properties such as arm length, steric bulk, solubility, or other physical properties.
  • monohydroxyamines include, but are not limited to:
  • 3-hydroxypiperidine also referred to as 3-piperidinol
  • n 1 to about 200
  • the activated carbonate ester is converted to the corresponding carbamate using a primary or secondary amine which acts as a "terminating" amine.
  • a primary or secondary amine which acts as a "terminating" amine.
  • a mono-protected diamine is employed.
  • the terminating amine is a mono-CBZ protected piperazine, since this compound provides a convenient secondary amine handle for adding functionality by acylation with other reactive groups such as haloacetyl, maleimidoyl, etc. depending on what is desired at the N- terminus.
  • Ethylenediamine and other diamines can function similarly.
  • preferred terminating amines include, but are not limited to those shown below, as well as mono- protected (e.g., mono-CBZ-protected) forms thereof: piperazine,
  • a particularly preferred terminating amines is mono-CBZ-protected piperazine:
  • any primary or secondary amine containing compound which contains a reactive conjugating group (such as those described above) or a biologically active molecule can be used to terminate the dendrimer and provide the terminal functionality that is desired.
  • a reactive conjugating group such as those described above
  • a biologically active molecule can be used to terminate the dendrimer and provide the terminal functionality that is desired.
  • amino alcohols would provide terminal hydroxyl groups
  • amino aldehydes would provide terminal aldehyde groups
  • amino acids would provide terminal carboxylic acids
  • aminothiols would provide terminal thiols.
  • valency platform molecules are provided which act as scaffolds to which one or more molecules may be covalently tethered to form a conjugate.
  • the present invention pertains to valency platform conjugates.
  • the valency platform is covalently linked to one or more biologically active molecules, to form a conjugate.
  • biologically active molecule is used herein to refer to molecules which have biological activity, preferably in vivo.
  • the biologically active molecule is one which interacts specifically with receptor proteins.
  • the valency platform is covalently linked to one or more oligonucleotides, to form a conjugate. In one embodiment, the valency platform is covalently linked to one or more peptides, to form a conjugate. In one embodiment, the valency platform is covalently linked to one or more polypeptides, to form a conjugate. In one embodiment, the valency platform is covalently linked to one or more proteins, to form a conjugate. In one embodiment, the valency platform is covalently linked to one or more antibodies, to form a conjugate. In one embodiment, the valency platform is covalently linked to one or more saccharides, to form a conjugate.
  • the valency platform is covalently linked to one or more polysaccharides, to form a conjugate. In one embodiment, the valency platform is covalently linked to one or more epitopes, to form a conjugate. In one embodiment, the valency platform is covalently linked to one or more mimotopes, to form a conjugate. In one embodiment, the valency platform is covalently linked to one or more drugs, to form a conjugate.
  • the biological molecule is first modified to possess a functionalized linker arm, to facilitate conjugation.
  • a functionalized linker arm is a polyethylene glycol disulfide, such as, for example:
  • One advantage of the valency platforms of the present invention is the ability to introduce enhanced affinity of the tethered biologically active molecules for their binding partners. Another advantage of the valency platforms of the present invention is the ability to facilitate crosslinking of multiple ligands, as is useful in B cell tolerance. Another advantage of the valency platforms of the invention is the ability to include functionality on the "core" that can be independently modified to enable the preparation of conjugates which can be tailored for specific purposes.
  • Conjugates of the valency platform molecule and one or more biologically active molecules may be prepared using known chemical synthetic methods.
  • the termini of the valency platform molecule i.e., the R A , R B , and/or R ⁇ of the group -
  • NR A R B preferably comprise a reactive conjugating functional group, and this reactive functional group may be used to couple the valency platform to the desired biologically active molecule.
  • the reactive haloacetyl group may be used to couple the valency platform to a biologically active molecule which possesses one or more reactive conjugating functional groups which are reactive towards the haloacetyl group, and which react to yield a covalent linkage.
  • the biologically active molecule is a protein which has one or more free amino groups (i.e., -NH 2 )
  • the two groups may be used to form the conjugate:
  • the biologically active molecule is a protein which has one or more free thiol groups (i.e., -SH) or sulfide groups (i.e., -SR), the two groups may be used to form the conjugate:
  • a terminal maleimidoyl group may be used to couple the valency platform to a biologically active molecule which possesses one or more reactive conjugating functional groups which are reactive towards the maleimidoyl group, and which react to yield a covalent linkage.
  • the biologically active molecule is a protein which has one or more free thiol groups (i.e., -SH) or sulfide groups (i.e., -SR), the two groups may be used to form the conjugate:
  • HEGA bis-hexaethyleneglycolamine
  • One hydroxy terminus of hexaethylene glycol is first converted to a tosyl group (compound 1), which is then converted to a bromo group (compound 2).
  • the resulting compound is then reacted with tosylamide to yield tosylated bis- hexaethyleneglycolamine (compound 3).
  • the tosyl group is then removed to yield the desired bis-hexaethyleneglycolamine (compound 4).
  • Compound 7 was prepared according to an existing literature procedure as shown below (Bondunov et al, J. Org. Chem. 1995, Vol. 60, pp. 6097-6102). 33.8 g (321 mmol) of aminodiethyleneglycol (compound 6), 9.4 g ( 88.3 mmol) of Na 2 CO 3 , 200 mL of toluene, and 10.0 g (80.3 mmol) of chlorotriethyleneglycol (compound 5), were refluxed with a Dean-Starke trap to remove water for 48 hours. The mixture was allowed to cool then filtered and concentrated. The resulting 45.8 g of material was vacuum distilled (bp 153- 158°C, 0.1 Torr) to yield 12.0 g (78%) of compound 7.
  • FIGS 11 A and 1 IB Compound.
  • the bis-hexaethyleneglycolamine (compound 4) was reacted with di-tert-butyldicarbonate to yield the N-BOC compound (compound 8), which was then reacted with/? ⁇ r ⁇ -nitrophenylchloroformate to yield the par a- nitrophenylcarbonate compound (compound 9).
  • the ⁇ r ⁇ -nitrophenylcarbonate (PNP) group was then converted to a carbamate group by reaction with mono-CBZ-protected piperazine, yielding compound jTj.
  • the BOC group was removed using trifluoroacetic acid to yield compound 1_1_.
  • FIG. 12A and 12B A chemical scheme for the preparation of an octamer of DEGA/TEG is shown in Figures 12A and 12B.
  • the bis-diethyleneglycolamine (compound 7) was reacted with di- tert-butyldicarbonate to yield the N-BOC compound (compound J_6), which was then reacted with > ⁇ r ⁇ -nitrophenylchloroformate to yield the ? ⁇ r ⁇ -nitrophenylcarbonate compound (compound 17).
  • the js ⁇ r ⁇ -nitrophenylcarbonate (PNP) group was then converted to a carbamate group by reaction with mono-CBZ-protected piperazine, yielding compound 1_8.
  • the BOC group was removed using trifluoroacetic acid to yield compound 18a.
  • Compounds 17 and ]_8a were then reacted together to form a "one-sided" dendritic compound (compound 19). Again, the BOC group was removed using trifluoroacetic acid to yield compound 19a.
  • Compound 19a was then reacted with triethyleneglycol bis chloroformate (from which the "core” is derived) to yield the "two-sided” dendritic compound (compound 20).
  • the terminal CBZ-protected amino groups were then converted to the hydrobromide salt of amino group, and further reacted with bromoacetic anhydride to yield reactive bromoacetyl groups at each of the termini in compound 20a.
  • compound 20 is treated with 30% HBr/AcOH for 30 min.
  • the resulting HBr salt is precipitated with ether.
  • the solids are collected by centrifugation and washed with ether.
  • the resulting HBr salt is dried in the desiccator overnight and dissolved in H 2 O.
  • the mixture was stirred at 0°C and sodium bicarbonate added.
  • a solution of bromoacetic anhydride in dioxane is added, and the mixture stirred at 0°C for 15-20 min.
  • To the mixture is added H 2 O, and the mixture is slowly acidified with 1 M H 2 SO 4 to a pH of 4.
  • the aqueous layer is extracted with EtOAc which was discarded.
  • the aqueous layer is then extracted with 8/2 CH 2 Cl 2 /MeOH.
  • the combined organic layers are dried (MgSO 4 ), filtered and concentrated to give compound 20a.
  • compound 23 is treated with 30% HBr/AcOH for 30 min.
  • the resulting HBr salt is precipitated with ether.
  • the solids are collected by centrifugation and washed with ether.
  • the resulting HBr salt is dried in the desiccator overnight and dissolved in H 2 O.
  • the mixture was stirred at 0°C and sodium bicarbonate added.
  • a solution of bromoacetic anhydride in dioxane is added, and the mixture stirred at 0°C for 15-20 min.
  • To the mixture is added H 2 O, and the mixture is slowly acidified with 1 M H 2 SO 4 to a pH of 4.
  • the aqueous layer is extracted with EtOAc which was discarded.
  • the aqueous layer is then extracted with 8/2 CH 2 Cl 2 /MeOH.
  • the combined organic layers are dried (MgSO 4 ), filtered and concentrated to give compound 23a.
  • FIG 14A The bis-diethyleneglycolamine (compound 7) was reacted with terephthaloyl chloride (from which the "core” is derived) to yield the tetrahydroxy compound, compound 24.
  • Compound 24 was then reacted with j o ⁇ r ⁇ -nitrophenylchloroformate to yield the tetra j9 ⁇ ra-nitrophenylcarbonate compound (compound 25).
  • the /? ⁇ r ⁇ -nitrophenylcarbonate (PNP) group was then converted to a carbamate group by reaction with mono-CBZ- protected piperazine, yielding compound 26.
  • the terminal CBZ-protected amino groups were then converted to the hydrobromide salt of amino group, and further reacted with bromoacetic anhydride to yield reactive bromoacetyl groups at each of the termini in compound 26a.
  • compound 26 is treated with 30% HBr/AcOH for 30 min.
  • the resulting HBr salt is precipitated with ether.
  • the solids are collected by centrifugation and washed with ether.
  • the resulting HBr salt is dried in the desiccator overnight and dissolved in H 2 O.
  • the mixture was stirred at 0°C and sodium bicarbonate added.
  • a solution of bromoacetic anhydride in dioxane is added, and the mixture stirred at 0°C for 15-20 min.
  • To the mixture is added H 2 O, and the mixture is slowly acidified with 1 M H 2 SO 4 to a pH of 4.
  • the aqueous layer is extracted with EtOAc which was discarded.
  • the aqueous layer is then extracted with 8/2 CH 2 Cl 2 /MeOH.
  • the combined organic layers are dried (MgSO 4 ), filtered and concentrated to give compound 26a.
  • FIG. 14B A chemical scheme for the preparation of an octamer of DEGA/PTH is shown in Figure 14B.
  • the bis-diethyleneglycolamine (compound 7) was reacted with the tetr ⁇ x para- nitrophenylcarbonate compound (compound 25) to yield the octahydroxy compound, compound 27a.
  • Compound 27a was then reacted withjc ⁇ r ⁇ -nitrophenylchloroformate to yield the octa ⁇ r ⁇ -nitrophenylcarbonate compound (compound 27).
  • the par a- nitrophenylcarbonate (PNP) group was then converted to a carbamate group by reaction with mono-CBZ-protected piperazine, yielding compound 28.
  • the terminal CBZ-protected amino groups were then converted to the hydrobromide salt of amino group, and further reacted with bromoacetic anhydride to yield reactive bromoacetyl groups at each of the termini in compound 28
  • compound 28 is treated with 30% HBr/AcOH for 30 min.
  • the resulting HBr salt is precipitated with ether.
  • FIG. 15 A chemical scheme for the preparation of an tetramer of HEGA/TEG is shown in Figure 15.
  • the bis-hexaethyleneglycolamine (compound 7) was reacted triethyleneglycol bis chloroformate (from which the "core” is derived) to yield the tetrahydroxy compound, compound 29.
  • Compound 29 was then reacted with /r ⁇ r ⁇ -nitrophenylchloro formate to yield the terra /j ⁇ r ⁇ -nitrophenylcarbonate compound (compound 30).
  • FIG. 16 A A chemical scheme for the preparation of an tetramer of DEGA/PTH is shown in Figure 16 A.
  • Diethanolamine was reacted with terephthaloyl chloride (from which the "core” is derived) to yield the tetrahydroxy compound, compound 32.
  • Compound 32 was then reacted with /? ⁇ r ⁇ -nitrophenylchloro formate to yield the tetra para- nitrophenylcarbonate compound (compound 33).
  • the r> ⁇ r ⁇ -nitrophenylcarbonate (PNP) group was then converted to a carbamate group by reaction with mono-CBZ-protected piperazine, yielding compound 34.
  • the terminal CBZ-protected amino groups were then converted to the hydrobromide salt of amino group, and further reacted with bromoacetic anhydride to yield reactive bromoacetyl groups at each of the termini in compound 34a.
  • compound 36 is treated with 30% HBr/AcOH for 30 min.
  • the resulting HBr salt is precipitated with ether.
  • the solids are collected by centrifugation and washed with ether.
  • the resulting HBr salt is dried in the desiccator overnight and dissolved in H 2 O.
  • the mixture was stirred at 0°C and sodium bicarbonate added.
  • a solution of bromoacetic anhydride in dioxane is added, and the mixture stirred at 0°C for 15-20 min.
  • To the mixture is added H 2 O, and the mixture is slowly acidified with 1 M H 2 SO 4 to a pH of 4.
  • the aqueous layer is extracted with EtOAc which was discarded.
  • the aqueous layer is then extracted with 8/2 CH 2 Cl 2 /MeOH.
  • the combined organic layers are dried (MgSO 4 ), filtered and concentrated to give compound 36a.
  • FIG. 17A and 17B A chemical scheme for the preparation of an tetramer of DEA/DEG is shown in Figures 17A and 17B.
  • Diethyleneglycol from which the "core” is derived
  • compound 37 was then reacted with diethanolamine to form the tetrahydroxy compound, compound 38.
  • compound 38 was then reacted with para- nitrophenylchloroformate to yield the tetra/? ⁇ ra-nitrophenylcarbonate compound (compound 39).
  • the precipitate, compound 41_ was dissolved in 20 mL of H 2 O.
  • the mixture was brought to pH 12 by addition of 10 N NaOH and extracted with six 20 mL portions of 4/1 CH 2 Cl 2 /MeOH.
  • the combined organic layers were dried (MgSO 4 ), filtered, and concentrated to provide the free amine.
  • the free amine was dissolved in 8 mL of CH 3 CN, 1.5 mL of MeOH was added to improve solubility, and the solution was stirred at 0°C while a solution of 114 mg (0.66 mmol) of chloroacetic anhydride in 2 mL of CH 3 CN was added.
  • the mixture was stirred at room temperature for 2.5 hours and concentrated to give 107 mg of an oil.
  • FIG. 17C and 17D A chemical scheme for the preparation of an octamer of DEA DEG is shown in Figures 17C and 17D.
  • the tetra/rar ⁇ -nitrophenylcarbonate compound, compound 39 was reacted with diethanolamine to form the octahydroxy compound, compound 43a.
  • Compound 43 a was then reacted with ? ⁇ r ⁇ -nitrophenylchloroformate to yield the octa ⁇ ra-nitrophenylcarbonate compound (compound 43).
  • the precipitate, compound 44a was dissolved in 20 mL of H 2 O.
  • the mixture was brought to pH 12 by addition of 10 N NaOH and extracted with six 20 mL portions of 4/1
  • FIG. 18A and 18B A chemical scheme for the preparation of an octamer of ADP/DEG is shown in Figures 18A and 18B.
  • the di-p ⁇ r ⁇ -nitrophenylcarbonate derivative of diethyleneglycol, compound 37 (from which the "core” is derived) was reacted with 2-amino-l,3- propanediol to yield the tetrahydroxy compound, compound 46.
  • Compound 46 was reacted with ⁇ r ⁇ -nitrophenylchloro formate to yield the tetra oro-nitrophenylcarbonate compound (compound 47).
  • Compound 47 was then reacted with 2-amino- 1,3 -propanediol to yield the octahydroxy compound, compound 47a.
  • Compound 47a was then reacted with para- nitrophenylchloro formate to yield the octa ?arfl-nitrophenylcarbonate compound
  • a solution of compound 37 in pyridine is added to a 0°C solution of 3 eq. of 2- amino- 1,3 -propanediol in pyridine.
  • the cooling bath is removed, and the mixture is stirred for 5 hours at room temperature.
  • Compound 46 can be isolated if desired, however, it is generally more convenient to isolate after forming the 4-nitrophenylcarbonate ester.
  • compound 48a is dissolved in 30%) HBr/HOAc. The mixture is stirred for 30 minutes at room temperature, and the HBr salt precipitated by addition of Et 2 O. The precipitate is washed with Et ⁇ O, and dried under vacuum.
  • the precipitate, compound 48b is dissolved in H 2 O.
  • the mixture is brought to pH 12 by addition of 10 N NaOH and extracted with 4/1 CH 2 Cl 2 /MeOH.
  • the combined organic layers are dried (MgSO 4 ), filtered, and concentrated to provide the free amine.
  • the free amine is dissolved in CH 3 CN, MeOH is added to improve solubility, and the solution is stirred at 0°C while a solution of chloroacetic anhydride in CH 3 CN is added.
  • the mixture was stirred at room temperature for 2 hours and concentrated to give crude compound 48c, which is purified by preparative
  • a solution of compound 50 is treated with 10 eq. of mono-N-BOC-ethylenediamine in pyridine and CH 2 C1 2 .
  • the mixture is stirred at room temperature until complete as evidenced by TLC, and partitioned between 1 N HCl and CH 2 C1 2 .
  • the combined organic layers is dried (MgSO 4 ), filtered, and concentrated to give crude product. Purification by silica gel chromatography (EtOAc/hexanes and CH 2 Cl 2 /MeOH) provides compound 51.
  • FIG. 20A and 20B A chemical scheme for the solid phase synthesis of a tetramer of octamer of DEA/DEG is shown in Figures 20A and 20B.
  • Wang resin having terminal hydroxy groups, was reacted with ⁇ r ⁇ -nitrophenylchloroformate to yield the par a- nitrophenylcarbonate compound (compound 52).
  • Compound 52 was then reacted with diethanolamine to form the dihydroxy compound, compound 52a.
  • Compound 52a was then reacted with ⁇ r ⁇ -nitrophenylchloro formate to yield the di » ⁇ r ⁇ -nitrophenylcarbonate compound (compound 52b).
  • The/> ⁇ r ⁇ -nitrophenylcarbonate (PNP) group was then converted to a carbamate group by reaction with mono-CBZ-protected piperazine, yielding compound 53.
  • the CBZ-protected compound was then cleaved from the resin, and reacted with diethyleneglycol bis chloroformate (from which the "core” is derived), to yield the tetra-CBZ-protected amino compound, compound 40.
  • the terminal CBZ-protected amino groups may be converted to the hydrobromide salt of amino group, and further reacted with chloroacetic anhydride to yield reactive chloroacetyl groups at each of the termini.
  • the resin was then suspended in 410 ⁇ L of CH 2 C1 2 , and 71 mg (0.673 mmol) of diethanolamine (410 ⁇ L of a solution of 82.5 mg of diethanolamine dissolved in 493 ⁇ L of pyridine). After gentle agitation of the mixture for 16 hours, the resin was washed with CH 2 C1 2 and dried, to yield compound 52a.

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Abstract

La présente invention concerne, de façon générale, des molécules de valences, telles que les molécules à plate-forme de valence servant d'échafaudages auxquelles une ou plusieurs molécules peuvent se lier de manière covalente pour former un conjugué. L'invention concerne notamment des molécules à plate-forme de valenceomprenant une liaison carbamate (-O-C(=O)(N∫). Dans un mode de réalisation, l'invention concerne des plates-formes de valence comportant des liaisons carbamate dont les molécules ont une structure de formule I, II ou III, comme d'après la figure 1. Dans un autre mode de réalisation l'invention concerne des plates-formes de valence comportant des liaisons carbamate dont les molécules ont une structure de formule IV, V ou VI, comme d'après la figure 8. Cette invention concerne également des procédés de préparation de telles molécules à plate-forme de valence, des conjugués comportant de telles molécules, et des procédés de préparation desdits conjugués.
PCT/US1999/029339 1998-12-09 1999-12-09 Echafaudages moleculaires comprenant des liaisons carbamate servant de modeles WO2000034231A1 (fr)

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AU20496/00A AU775925B2 (en) 1998-12-09 1999-12-09 Molecular scaffolds acting as templates comprising carbamate linkages
CA002353462A CA2353462A1 (fr) 1998-12-09 1999-12-09 Echafaudages moleculaires comprenant des liaisons carbamate servant de modeles
KR1020017007221A KR20010093813A (ko) 1998-12-09 1999-12-09 카르바메이트 결합을 포함하는 템플레이트로서 작용하는분자 스캐폴드
EP99964209A EP1137628A1 (fr) 1998-12-09 1999-12-09 Echafaudages moleculaires comprenant des liaisons carbamate servant de modeles
JP2000586680A JP2002531541A (ja) 1998-12-09 1999-12-09 カルバメート結合を含むテンプレートとして作用する分子足場

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US09/457,607 1999-12-08
US09/457,607 US6458953B1 (en) 1998-12-09 1999-12-08 Valency platform molecules comprising carbamate linkages

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